Due to their accumulation in diseased over healthy tissue and their fluorescing properties, porphyrinic pigments have emerged as promising, minimally invasive drug candidates in the detection and treatment of neoplastic and non-neoplastic diseases. In spite of their great potential in malignancy treatment, to date only six compounds received regulatory approval, all of them as photosensitizers for photodynamic therapy (PDT). However, due to the severe shortcomings of these drugs, leading scientists at photodynamic therapy conferences in 2003 and 2005 urged the community to design more effective photodrugs. In response to this need, the proposed research is aimed at rational porphyrinic drug design with the long-term goal to understand how photosensitizers have to be designed to enhance their efficacy and selectivity. In pursuit of this goal, it is the hypothesis that the design of more effective photosensitizers requires their selective uptake and localization in mitochondria as these organelles are not only the powerhouse of the cell, but also at the center of cell death. To test this hypothesis, the specific aims are to: I. Synthesize porphyrinic pigments and their metal complexes with recognized mitochondrial targeting characteristics. We propose to prepare (a) porphyrins, chlorins, and phthalocyanines with carefully selected properties and (b) related aluminum(lll), gallium(lll), indium(lll), and zinc(ll) complexes. II. Determine the ability of the porphyrinic pigments and their metal complexes to target mitochondria. To uncover how structural features of the proposed photosensitizers will influence mitochondrial and cellular uptake, we will (a) measure their partition coefficients to predict uptake and photosensitizing outcomes and (b) determine their uptake in functional vesicles, and when successful, in isolated mitochondria and cancer cell mitochondria to assess their mitochondrial targeting selectivity. III. Determine the photosensitizing efficiency of the porphyrinic pigments and their metal complexes. To better understand how structural characteristics of the proposed drug candidates will define their photosensitizing and phototoxic activities, we propose to determine (a) their abilities to cause oxidative damage to isolated mitochondria and cancer cells, and (b) their photophysical and phototoxic properties. Relevance to Public Health: This project is to determine how photodrugs have to be designed to target mitochondria, which will have far-reaching consequences for disease-specific therapeutic approaches. The studies hold the promise to empower PDT to turn into a clinically viable alternative in the simultaneous detection, diagnosis, and treatment of diseases and to provide clinicians with a viable alternative in the fight against cancer.